This proposal describes a tailored basic research training program for the transition from post-doctoral fellow to independent investigator. The principal investigator has a Ph.D. in Cell Biology, completed a structured residency training program in Internal Medicine and two years of clinical training in Cardiology which is being followed by three years of research training. There is a heart attack every 30 seconds in the United States. Ischemic heart disease leading to myocardial infarction and heart failure is one of most pressing health care issues and highest research priorities. With few treatment options, the clinical prognosis of ischemic heart disease is dismal. The central issue is that the heart cannot regenerate heart muscle cells to restore its pump function after a heart attack. Therefore, there is great demand to develop therapeutic strategies to build new heart muscle. Recent works illustrate that a fully differentiated cell type can convert to another by small set of transcription factors. Using this new reprogramming technique, the research work proposed in this project will focus on designing efficient strategies to make new heart muscle cells from the most abundant ordinary tissue cells through genetic and pharmacologic manipulation, and test their potential for clinical use as a post-heart attack therapy. The specific aims include the following: 1) To determine whether enhancing Mef2c activity increases reprogramming efficiency, 2) To assess the ability of a select subset of small molecules to enhance cardiac lineage reprogramming and to replace reprogramming factors, 3) To assess the efficacy of in vivo reprogramming by delivery of reprogramming factors in a rodent MI model. The proposal described herein will provide a unique opportunity to develop new strategies for cardiac repair and to understand the molecular basis of the reprogramming of cellular identity. In this regard, Dr. Eric Olson, the chairman of Molecular Biology at the University of Texas Southwestern at Dallas and a world authority in the field, will serve as the ideal mentor. He has trained numerous post-doctoral fellows in the past and has sponsored previous and current physician-scientists. Furthermore, a scientific advisory committee has been proposed that will not only provide regular constructive criticism of data, hypotheses, and proposed experiments but invaluable advice regarding career development as an independent and productive physician- scientist. It is also expected that the members of the advisory committee will be invaluable in offering their expertise and unique reagents to foster this research plan. The combination of the Molecular Biology and Cardiology departments will provide the ideal interdisciplinary setting not only to conduct the proposed experiments, but to develop as an independent physician-scientist. PUBLIC HEALTH RELEVANCE: Ischemic heart disease is the leading cause of morbidity and mortality in the United States. The fundamental problem comes from the fact that the heart cannot regenerate heat muscle cells once they are lost after heart attack. Through this work we will design a new strategy to make new heart muscle cells from the most abundant tissue cells in the heart and validate its therapeutic potential.